OBJECTIVE: De novo mutations of the gene sodium channel 1α (SCN1A) are the major cause of Dravet syndrome, an infantile epileptic encephalopathy. US incidence of DS has been estimated at 1 in 40 000, but no US epidemiologic studies have been performed since the advent of genetic testing. METHODS: In a retrospective, population-based cohort of all infants born at Kaiser Permanente Northern California during 2007–2010, we electronically identified patients who received ≥2 seizure diagnoses before age 12 months and who were also prescribed anticonvulsants at 24 months. A child neurologist reviewed records to identify infants who met 4 of 5 criteria for clinical Dravet syndrome: normal development before seizure onset; ≥2 seizures before age 12 months; myoclonic, hemiclonic, or generalized tonic-clonic seizures; ≥2 seizures lasting >10 minutes; and refractory seizures after age 2 years. SCN1A gene sequencing was performed as part of routine clinical care. RESULTS: Eight infants met the study criteria for clinical Dravet syndrome, yielding an incidence of 1 per 15 700. Six of these infants (incidence of 1 per 20 900) had a de novo SCN1A missense mutation that is likely to be pathogenic. One infant had an inherited SCN1A variant that is unlikely to be pathogenic. All 8 experienced febrile seizures, and 6 had prolonged seizures lasting >10 minutes by age 1 year. CONCLUSIONS: Dravet syndrome due to an SCN1A mutation is twice as common in the United States as previously thought. Genetic testing should be considered in children with ≥2 prolonged febrile seizures by 1 year of age.
BackgroundEnvironmental exposures that occur in utero and during early life may contribute to the development of childhood asthma through alteration of the human microbiome. The objectives of this study were to estimate the cumulative effect and relative importance of environmental exposures on the risk of childhood asthma.MethodsWe conducted a population-based birth cohort study of mother-child dyads who were born between 1995 and 2003 and were continuously enrolled in the PRIMA (Prevention of RSV: Impact on Morbidity and Asthma) cohort. The individual and cumulative impact of maternal urinary tract infections (UTI) during pregnancy, maternal colonization with group B streptococcus (GBS), mode of delivery, infant antibiotic use, and older siblings at home, on the risk of childhood asthma were estimated using logistic regression. Dose-response effect on childhood asthma risk was assessed for continuous risk factors: number of maternal UTIs during pregnancy, courses of infant antibiotics, and number of older siblings at home. We further assessed and compared the relative importance of these exposures on the asthma risk. In a subgroup of children for whom maternal antibiotic use during pregnancy information was available, the effect of maternal antibiotic use on the risk of childhood asthma was estimated.ResultsAmong 136,098 singleton birth infants, 13.29% developed asthma. In both univariate and adjusted analyses, maternal UTI during pregnancy (odds ratio [OR] 1.2, 95% confidence interval [CI] 1.18, 1.25; adjusted OR [AOR] 1.04, 95%CI 1.02, 1.07 for every additional UTI) and infant antibiotic use (OR 1.21, 95%CI 1.20, 1.22; AOR 1.16, 95%CI 1.15, 1.17 for every additional course) were associated with an increased risk of childhood asthma, while having older siblings at home (OR 0.92, 95%CI 0.91, 0.93; AOR 0.85, 95%CI 0.84, 0.87 for each additional sibling) was associated with a decreased risk of childhood asthma, in a dose-dependent manner. Compared with vaginal delivery, C-section delivery increased odds of childhood asthma by 34% (OR 1.34, 95%CI 1.29, 1.39) in the univariate analysis and 11% after adjusting for other environmental exposures and covariates (AOR 1.11, 95%CI 1.06, 1.15). Maternal GBS was associated with a significant increased risk of childhood asthma in the univariate analysis (OR 1.27, 95%CI 1.19, 1.35), but not in the adjusted analysis (AOR 1.03, 95%CI 0.96, 1.10). In the subgroup analysis of children whose maternal antibiotic use information was available, maternal antibiotic use was associated with an increased risk of childhood asthma in a similar dose-dependent manner in the univariate and adjusted analyses (OR 1.13, 95%CI 1.12, 1.15; AOR 1.06, 95%CI 1.05, 1.08 for every additional course). Compared with infants with the lowest number of exposures (no UTI during pregnancy, vaginal delivery, at least five older siblings at home, no antibiotics during infancy), infants with the highest number of exposures (at least three UTIs during pregnancy, C-section delivery, no older siblings, eight or mor...
To quantify the relationship between recurrent wheezing (RW) in the third year of life and respiratory syncytial virus (RSV) infection, prematurity, and neonatal oxygen exposure. Design: Retrospective cohort study linking inpatient, outpatient, and laboratory databases for cohort assembly and logistic regression analysis. Setting: Integrated health care delivery system in Northern California. Participants: A total of 71 102 children born from 1996 to 2002 at 32 weeks' gestational age or later who were health plan members for 9 or more months in their first and third years. Main Exposures: Laboratory-confirmed, medically attended RSV infection during first year and supplemental oxygen during birth hospitalization. Outcome Measures: Recurrent wheezing, quantified through outpatient visits, inpatient hospital stays, and asthma prescriptions. Results: The rate of RW in the third year of life was 16.23% among premature infants with RSV and 6.22% among those without RSV. The risk of RW increased among infants who had an RSV outpatient encounter (adjusted odds ratio [AOR], 2.07; 95% CI, 1.61-2.67), uncomplicated RSV hospitalization (AOR, 4.66; 95% CI, 3.55-6.12), or prolonged RSV hospitalization (AOR, 3.42; 95% CI, 2.01-5.82) compared with infants without RSV encounters. Gestational age of 34 to 36 weeks was associated with increased risk of RW (AOR, 1.23; 95% CI 1.07-1.41) compared with 38 to 40 weeks, while a gestational age of 41 weeks or more was protective (AOR, 0.90; 95% CI, 0.81-0.99). Supplemental oxygen exposure was associated with increased risk at all levels. Conclusion: Laboratory-confirmed, medically attended RSV infection, prematurity, and exposure to supplemental oxygen during the neonatal period have independent associations with the development of RW in the third year of life.
Background Respiratory syncytial virus (RSV) lower respiratory tract infection is implicated in asthma development. RSV immunoprophylaxis during infancy is efficacious in preventing RSV hospitalizations and has been associated with decreased wheezing in the first years of life. Objective We investigated whether greater adherence to immunoprophylaxis in infants at high-risk for severe RSV would be associated with decreased childhood asthma. Methods We conducted a retrospective cohort investigation including children born 1996-2003, enrolled in Kaiser Permanente Northern California or Tennessee Medicaid, and eligible to receive RSV immunoprophylaxis. Asthma was defined at 4.5-6 years using asthma-specific healthcare visits and medication fills. We classified children into immunoprophylaxis eligibility groups and calculated adherence (% receipt of recommended doses). We employed a set of statistical strategies (multivariable logistic regression, propensity score (PS)-adjusted and-matched analyses) to overcome confounding by medical complexity, as infants with higher adherence (≥70%) have higher prevalence of chronic lung disease, lower birth weight, and longer nursery stays. Results Using multivariable logistic regression and PS-adjusted models in the combined group, higher adherence to RSV immunoprophylaxis was not associated with decreased asthma. However in PS-matched analysis, treated children with ≥70% adherence had decreased odds of asthma compared to those with ≤20% adherence (odds ratio 0.62: 95% CI 0.50, 0.78). Conclusions This investigation of RSV immunoprophylaxis in high-risk children primarily found non-significant associations on prevention of asthma in specific preterm groups. Findings highlight need for larger studies, prospective cohorts, and provide estimates of potential preventive effect sizes in high-risk children.
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